Study of AZD2014 and Palbociclib in Patients With Estrogen Receptor Positive (ER+) Metastatic Breast Cancer
- Conditions
- Advanced and Metastatic Breast Cancer
- Interventions
- Registration Number
- NCT02599714
- Lead Sponsor
- AstraZeneca
- Brief Summary
This dose finding/extension study was designed originally to consist of three parts: Part A was intended to identify the MTD of the AZD2014/ palbociclib combination on a background of fulvestrant (referred to as the triplet) in postmenopausal women with locally advanced/ metastatic estrogen receptor positive (ER+) breast cancer. Part B was to further characterize safety, tolerability, PK, and preliminary efficacy in single-arm dose expansion groups. Part C was to be a Phase 2, randomized, double-blind, extension comparing the triplet and doublet combinations. Part C was deleted from the protocol and was not performed.
- Detailed Description
This dose finding/extension study was designed originally to consist of three parts:
Part A is a Phase 1 triplet-dose finding investigation in 3-6 patients per cohort to determine the maximum tolerated dose (MTD) of the triplet.
Part B is a single arm expansion in approximately 27 patients evaluable for response to define the recommended Phase 2 dose (RP2D).
Part C was intended to investigate the efficacy of the triplet combination at the RP2D in a randomized, double-blind, placebo-controlled, stratified, parallel group extension. Part C was intended to include ER+, locally advanced and/or metastatic breast cancer patients who have progressed following prior non-steroidal aromatase inhibitor (NSAI) endocrine therapy. Patients in Part C were to be randomized to receive either the triplet combination (AZD2014 + palbociclib + fulvestrant) or the doublet (matching AZD2014 placebo + palbociclib + fulvestrant). Patients were to be stratified according to hormone sensitivity, presence of visceral metastases, and prior CDK inhibitor treatment. Part C would have been conducted if indicated by the emerging data.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 54
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Triplet Combination (Dose Finding) AZD2014 Phase 1 triplet dose finding phase in 3-6 patients per cohort - approximately 30 patients depending on emerging data to determine the maximum tolerated dose (MTD) of the triplet. Triplet Combination (Dose Expansion) AZD2014 Additional patients will be enrolled at the dose determined in Part A. Triplet Combination (Dose Finding) Palbociclib Phase 1 triplet dose finding phase in 3-6 patients per cohort - approximately 30 patients depending on emerging data to determine the maximum tolerated dose (MTD) of the triplet. Triplet Combination (Dose Finding) Fulvestrant Phase 1 triplet dose finding phase in 3-6 patients per cohort - approximately 30 patients depending on emerging data to determine the maximum tolerated dose (MTD) of the triplet. Triplet Combination (Dose Expansion) Palbociclib Additional patients will be enrolled at the dose determined in Part A. Triplet Combination (Dose Expansion) Fulvestrant Additional patients will be enrolled at the dose determined in Part A.
- Primary Outcome Measures
Name Time Method Parts A and B: Number of adverse events experienced by patients Approximately 16 months Safety and tolerability assessed through the incidence of adverse events.
- Secondary Outcome Measures
Name Time Method Part B: Duration of Response (DoR) Assessed every 8 weeks for approximately 16 months DoR assessed as the time between disease response being achieved and progressive disease as assessed by RECIST 1.1 criteria or end of life (in the absence of progression)
Parts A and B: Peak plasma concentrations (Cmax) of AZD2014 and palbociclib following multiple doses Samples will be collected at prespecified time points up to 12 hours following dosing. Venous blood samples (2 mL for each drug) for determination of concentrations of AZD2014 and palbociclib in plasma will be collected.
Time to reach peak plasma concentrations (tmax) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 12 hours following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. Tmax is the time required after administration for the drug to reach its peak plasma concentration.
Part B: Overall Survival (OS) Approximately 24 months The time from start of treatment until end of life from any cause.
Parts A and B: Best Objective Response (BOR) Assessed every 8 weeks for approximately 16 months BOR assessed according to RECIST 1.1 criteria by Investigator assessment.
Part A: Peak plasma concentrations (Cmax) of AZD2014 and palbociclib following single dose Samples for single dose PK will be collected at prespecified time points up to 12 hours following dosing. Venous blood samples for determination of concentrations of AZD2014 and palbociclib in plasma will be collected.
Area under the plasma concentration-time curve from zero to infinity (AUC 0-∞) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 9 days following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. Area under the curve is the integral of the concentration-time curve. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration. The area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
Area under the plasma concentration-time curve from zero to 12 hours (AUC 0-12) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 12 hours following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. Area under the curve is the integral of the concentration-time curve. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration. The area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
Area under the plasma concentration-time curve from zero to 24 hours (AUC 0-24) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 24 hours following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. Area under the curve is the integral of the concentration-time curve. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration. The area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
Area under the plasma concentration-time curve from zero to the last measurable concentration (AUC 0-t) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 9 days following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. Area under the curve is the integral of the concentration-time curve. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration. The area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
Part B: Progression Free Survival (PFS) Assessed every 8 weeks for approximately 16 months PFS assessed through change in tumour size (as well as assessment of non-target lesions and appearance of any new lesions) according to RECIST 1.1 criteria by Investigator assessment.
Parts A and B: Objective Response Rate (ORR) Assessed every 8 weeks for approximately 16 months ORR assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) according to RECIST 1.1 criteria
Parts A and B: Change from baseline in biomarker H-score 16 months For those subjects with paired tumour biopsies the pharmacodynamic markers will be assessed by immunohistochemistry.
Terminal elimination rate constant (λz) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 9 days following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. The elimination rate constant is the rate at which drug is cleared from the body assuming first-order elimination
Terminal plasma half-life (t1/2λz) for AZD 2014 and palbociclib. Samples will be collected at prespecified time points up to 9 days following dosing. The plasma concentrations of AZD2014 and palbociclib will be determined. The terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.
Trial Locations
- Locations (1)
Research Site
🇬🇧London, United Kingdom